Phase II clinical study of BBR 3464, a novel, bifunctional platinum analogue, in patients with advanced ovarian cancer

Calvert, A. H.; Thomas, Hilary; Colombo, N.; Gore, M.; Earl, HM; Sena, L. M.; Camboni, Gabriella; Liati, P.; Sessa, Cristiana

doi:10.1016/s0959-8049(01)81457-x

Cited by 40 publications

(86 citation statements)

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Section: New Platinum Agentsmentioning

confidence: 99%

“…Phase I studies show diarrhoea and neutropenia to be dose-limiting toxicities, without significant nephro-, neuro-or pulmonary toxicity (Calvert et al, 1999;Sessa et al, 2000). Antitumour activity was observed in colorectal and pancreatic cancer patients after a one-hour infusion of 1.1 mg m 72 every 28 days (Calvert et al, 1999). A second study (Sessa et al, 2000) showed similar toxicity (0.03 -0.17 mg m 72 day 71 for 5 days, repeated every 28 days), in patients with solid tumours unresponsive to previous antitumour treatment.…”

Section: New Platinum Agentsmentioning

confidence: 99%

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Platinum drugs in the treatment of non-small-cell lung cancer

Cosaert

Quoix

2002

Br J Cancer

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The use of chemotherapy is considered standard therapy in patients with locally advanced non-small-cell lung cancer that cannot be treated with radiotherapy and in those with metastatic non-small-cell lung cancer and good performance status. This approach is also accepted in patients with earlier stage disease, when combined with radiotherapy in those with nonresectable locally advanced disease, or in the preoperative setting. Randomised clinical studies and meta-analyses of the literature have confirmed the beneficial survival effect of platinum-based chemotherapy. Cisplatin and carboplatin have been successfully used with other drugs in a wide variety of well-established two-drug combinations while three-drug combinations are still under investigation. Cisplatin and carboplatin use is limited by toxicity and inherent resistance. These considerations have prompted research into new platinum agents, such as the trinuclear platinum agent BBR3464, the platinum complex ZD0473 and oxaliplatin. These compounds could be developed in combination with agents such as paclitaxel, gemcitabine or vinorelbine in patients with advanced and/or refractory solid tumours.

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Section: New Platinum Agentsmentioning

confidence: 99%

Section: New Platinum Agentsmentioning

confidence: 99%

Platinum drugs in the treatment of non-small-cell lung cancer

Cosaert

Quoix

2002

Br J Cancer

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“…Although there is the possibility that the use of single patient cohorts could be hazardous if there was a large amount of intrapatient variability in tolerance, this does not seem to have been the case in practice. In the author's experience, this design permitted the completion of a phase I study of a novel platinum analogue using only 10 patients (20). The article describing the design (19) has been cited 149 times since its publication in 1997, and it is likely that many other phase I trials have been based on the same concepts.…”

Section: The Traditional Phase I Trialmentioning

confidence: 99%

The Development of Phase I Cancer Trial Methodologies: the Use of Pharmacokinetic and Pharmacodynamic End Points Sets the Scene for Phase 0 Cancer Clinical Trials

Calvert¹,

Plummer²

2008

Clinical Cancer Research

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Although the concept of a phase 0 trial is a relatively new one, there has been a slowly increasing trend toward basing early clinical trial designs on pharmacokinetic and pharmacodynamic end points that has been developing over many years. This article will review the early cancer trial methodologies and the various techniques that have been used to refine them. Several illustrative examples will be presented showing their relevance to trial designs using pharmacodynamic end points and targeted agents. Some criteria for characterizing suitable phase 0 end points are suggested. Four trial designs that are essentially developed for cytotoxic agents using the maximal tolerated dose as an end point are described. Although these trials were not designed with the use of more sophisticated pharmacodynamic end points (such as the measurement of the effect of a targeted agent on its target), they have been developed to optimize the speed with which a dose needed to achieve a particular effect can be determined and are, to this extent, relevant to the design of studies with pharmacodynamic end points. The Traditional Phase I TrialThe phase I trial designs for anticancer agents have, in the past, differed from those of other therapeutic agents. Because most anticancer agents were antiproliferative agents, they had potentially life-threatening side effects to proliferating normal tissues such as the bone marrow and the gastrointestinal epithelium. Further, because the biochemical or biological differences between normal and tumor tissues are small, these drugs have a low therapeutic index, so that it is necessary to use a maximally tolerated dose (from the point of view of toxicity) to elicit any anticancer effect. For example, phase I trial of an antihypertensive agent would be done on normal volunteers and have a pharmacodynamic end point, the reduction in blood pressure. Although a phase I trial of an anticancer agent involves escalating doses to a defined end point, there are a number of differences. It would typically be done in cancer patients with a limited prognosis because of the concern of the potential genotoxicity of most of the anticancer agents. The end point of the trial would be toxicity to ensure that the maximally tolerated dose was used in phase II, which, in turn, would maximize the probability of seeing an anticancer effect. A further complication is that there is considerable interpatient variability in the tolerance of anticancer drugs.The traditional design for a phase I study of an anticancer agent arose from this background. A starting dose is selected, designed to be safe based on animal toxicology studies. Patients are treated in cohorts, normally of three, to allow some idea of interpatient variability to be obtained. Doses are escalated to a maximum tolerated dose (MTD), defined by toxicity. The size of the increments between successive dose levels is progressively decreased as toxicity is seen, frequently using a progression known as a modified Fibonacci series (although it bears lit...

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“…BBR3464 is also able to overcome acquired resistance in a panel of human cancer cell lines 9 . Unfortunately, the increased activity of BBR3464 is matched by 50-to 100-fold higher toxicity, which limits its use [10][11][12] . It is also easily degraded in the body, meaning little of the drug reaches cancer nuclei intact 9 .…”

Section: Introductionmentioning

confidence: 99%

Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents

Apps

Johnson

Sutcliffe

et al. 2014

JoVE

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Amide coupling reactions can be used to synthesize bispyridine-based ligands for use as bridging linkers in multinuclear platinum anticancer drugs. Isonicotinic acid, or its derivatives, are coupled to variable length diaminoalkane chains under an inert atmosphere in anhydrous DMF or DMSO with the use of a weak base, triethylamine, and a coupling agent, 1-propylphosphonic anhydride. The products precipitate from solution upon formation or can be precipitated by the addition of water. If desired, the ligands can be further purified by recrystallization from hot water. Dinuclear platinum complex synthesis using the bispyridine ligands is done in hot water using transplatin. The most informative of the chemical characterization techniques to determine the structure and gross purity of both the bispyridine ligands and the final platinum complexes is 1 H NMR with particular analysis of the aromatic region of the spectra (7-9 ppm). The platinum complexes have potential application as anticancer agents and the synthesis method can be modified to produce trinuclear and other multinuclear complexes with different hydrogen bonding functionality in the bridging ligand. Video LinkThe video component of this article can be found at

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Phase II clinical study of BBR 3464, a novel, bifunctional platinum analogue, in patients with advanced ovarian cancer

Cited by 40 publications

References 0 publications

Platinum drugs in the treatment of non-small-cell lung cancer

Platinum drugs in the treatment of non-small-cell lung cancer

The Development of Phase I Cancer Trial Methodologies: the Use of Pharmacokinetic and Pharmacodynamic End Points Sets the Scene for Phase 0 Cancer Clinical Trials

Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents

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